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We have finally sequenced the complete human genome. No, for real this time.

When scientists first announced that they had read all of a person鈥檚 DNA 20 years ago, they were still missing some bits. Now, with the benefit of far better methods for reading DNA, it has finally been possible to read the whole thing from end to end.

鈥淗aving been part of the original Human Genome Project in 2001, and especially focused on the difficult regions, it鈥檚 really satisfying for me to see this done even though it took 20 years,鈥� says at the University of Washington in Seattle.

The new genome includes an additional 200 million base pairs or 鈥渓etters鈥� of DNA, and adds more than 2000 extra genes.

Our genes help make us who we are. Humans have thousands of them, although the exact number is uncertain and partly depends on how you count them. They are stored on long molecules of DNA in the centres of cells. The genetic information exists as four molecules called bases (C, G, T and A) that are strung along the DNA molecule.

The human genome contains just over 3 billion letters. The first complete sequences were published to huge fanfare in 2001: (HGSC) and . The project had begun a decade before in 1990.

Because the genome had to be read in small chunks and then reassembled, some highly repetitive sections proved impossible to place, a bit like a jigsaw where all the pieces look alike.

Missing parts

Over the next three years, the HGSC filled in some of the gaps, and in 2004, the consortium announced that it had done all it could. Geneticists have continued to improve the reference genome, but largely by improving the accuracy of existing sequences, rather than by adding new ones. About 8 per cent was still either missing or likely to be wrong.

The new version of the genome has been created by the Telomere-to-Telomere consortium, led by at the University of California, Santa Cruz, and at the National Human Genome Research Institute in Maryland. In 2018, they were part of a team that sequenced big chunks of the genome, more than 100,000 bases long, enabling them to fill in some missing parts. 鈥淪he [Miga] called me up and said 鈥業 want to finish the genome鈥�,鈥� says Phillippy. 鈥淚 said, 鈥業 do too鈥�.鈥�

They chose to read the DNA from a cell line called CHM13. It comes from a mass of tissue called a hydatidiform mole, a kind of failed pregnancy in which an egg in a uterus somehow lost its genome, and was then fertilised by a sperm. The resulting cell only had half the DNA of a normal embryo, so the sperm鈥檚 DNA was duplicated. Such cells form dangerous growths, like cancers, and have to be removed. They can then be grown in the lab 鈥� seemingly indefinitely.

鈥淚t鈥檚 unique in this way, in that it鈥檚 not the genome of anyone who ever lived,鈥� says Phillippy. The DNA came from a single sperm, so it is half the genome of a potential father, which has been duplicated.

The cells were collected consensually several decades ago, but the identity of the donor was anonymised by a company that has since gone out of business, so it isn鈥檛 known from whom they came.

鈥淲e can鈥檛 really figure out [even] if we wanted to who it was from originally,鈥� says Phillippy.

Normal human cells have two copies of every stretch of DNA, which often have significant differences because one comes from the mother and one from the father. This makes it harder to sequence the DNA accurately, because it鈥檚 tricky to tell what is a mistake in sequencing and what is a genuine difference. Using CHM13 avoids this problem, because the two copies are virtually identical.

Complementary sequencing techniques

To assemble the genome鈥檚 sequences, the team combined two technologies. One was a type of sequencing that reads extremely long stretches, over a million letters long, and the other was a type that delivers extremely high accuracy and can thus handle sections that are very slightly different 鈥� such as multiple copies of the same gene.

Human DNA is stored on large molecules called chromosomes that have four arms joined in the centre to form an X shape. Much of the hard-to-read DNA was from around the central points, known as centromeres. Furthermore, some chromosomes are lopsided, with one pair of arms shorter than the other: the short arms contain a lot of difficult DNA.

As a first pass, in August 2020, the team published the complete human sex-determining X chromosome. They have now released the entire human genome.

The new version adds nearly 200 million letters to the previous version, with 2226 sections that are near-identical copies of known genes. Of these new genes, the team predicts that 115 code for proteins.

What is a gene?

Phillippy emphasises that these numbers are uncertain. 鈥淭he definition of what is a gene is still a bit messy,鈥� he says. Genes were traditionally thought of as sections of DNA that code for a protein, but in fact, many genes are non-coding and have other functions. The new genome has 63,494 genes, compared with 60,090 in . Genes that code proteins number 19,969, up from 19,890.

鈥淚t鈥檚 much, much better than anything we had,鈥� says at University College London.

In a second paper, Eichler鈥檚 team has focused on segmental duplications: long stretches of DNA that have been copied again and again. Unlike 鈥�junk DNA鈥�, which is often seemingly meaningless repetitions, segmental duplications include genes and other sequences that have recognisable functions. Because of them, people can have many copies of some genes.

Segmental duplications accounted for nearly one-third of the new sequence, and make up 7 per cent of the genome. Their sequences also varied more than non-duplicated regions did.

Eichler thinks segmental duplications have played a key role in human evolution. 鈥淭hey are the place in the genome where new genes are likely to be born,鈥� he says, because one of the copies is free to vary. Humans have several duplicated genes, which he says were seemingly 鈥渃ritical in building a bigger brain that distinguishes us from other apes鈥�.

Even if the duplicated genes don鈥檛 become significantly different, they can still have profound effects if they simply mean a protein gets made in larger quantities, says Andr茅s. She says segmental duplications cannot explain all of human evolution, because it was surely a hugely complex process, 鈥渂ut they are important鈥�.

Turning DNA on and off

The new genome will make it much easier to study duplicated genes, says Andr茅s, because the sequences it lists for them are much more likely to be correct than earlier versions.

It is crucial to understand segmental duplications because some of them underpin genetic disorders, says Eichler.

In a third paper, a team led by Winston Timp at Johns Hopkins University in Baltimore has examined marker chemicals called methyl groups that attach to DNA at various points. These 鈥渆pigenetic鈥� markers affect which genes are turned on and off. Timp鈥檚 team used the new genome to map methylation in the newly explored areas.

They found that levels of methylation are low around the centromeres at the heart of the chromosomes. These regions are crucial for reproduction and cell division.

When this goes wrong, the results can be dangerous. 鈥淚n cancer, you will often gain an entire chromosome or lose an entire chromosome,鈥� says Timp. In the long run, understanding how cell division works, and the role methylation might play, could point the way towards new cancer treatments.

References: bioRxiv, DOI: ; bioRxiv, DOI: ; bioRxiv, DOI: